Vascular development in the retina and inner ear: Control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair
Vascular development in the retina and inner ear: Control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair
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DOI：
10.1016/s0092-8674(04)00216-8
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发表时间：
2004-03-19
期刊：
影响因子：
64.5
通讯作者：
Nathans, J
中科院分区：
文献类型：
--
作者：
Xu, Q;Wang, YS;Nathans, J
视网膜血管化不完全发生在诺里病和家族性渗出性玻璃体视网膜病变（FEVR）中。Norrin是Norrie病基因的蛋白产物，是一种生化功能未知的分泌蛋白。FEVR的一种形式是由frzzled4 （Fz4）的缺陷引起的，Fz4是一种假定的Writ受体。我们在此表明，Norrin和Fz4作为配体受体对的功能是基于(1)人类和小鼠中Norrin和Fz4突变引起的血管表型的相似性，(2)Norrin-Fz4结合的特异性和高亲和力，(3)Norrin诱导Fz4和lrp依赖的经典Wnt通路激活的高效率，以及(4)Norrin和Fz4的疾病相关变体所显示的信号缺陷。这些数据确定了Norrin-Fz4信号系统在眼和耳的血管发育中起核心作用，并且它们表明与Writs无关的配体可以通过Fz受体起作用。
Incomplete retinal vascularization occurs in both Norrie disease and familial exudative vitreoretinopathy (FEVR). Norrin, the protein product of the Norrie disease gene, is a secreted protein of unknown biochemical function. One form of FEVR is caused by defects in Frizzled-4 (Fz4), a presumptive Writ receptor. We show here that Norrin and Fz4 function as a ligand-receptor pair based on (1) the similarity in vascular phenotypes caused by Norrin and Fz4 mutations in humans and mice, (2) the specificity and high affinity of Norrin-Fz4 binding, (3) the high efficiency with which Norrin induces Fz4- and Lrp-dependent activation of the classical Wnt pathway, and (4) the signaling defects displayed by disease-associated variants of Norrin and Fz4. These data define a Norrin-Fz4 signaling system that plays a central role in vascular development in the eye and ear, and they indicate that ligands unrelated to Writs can act through Fz receptors.